With an aging population and chronic liver disease becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to improve our understanding of the dynamics of innate and adaptive immune responses during chronic viral infection and the relationship of these responses to viral clearance. As the innate immune response is the first line of defense against pathogens, it is imperative to elucidate how aging modifies innate immunity and contributes to chronic viral persistence. Plasmacytoid dendritic cells (pDCs) play a pivotal role in detection of foreign pathogens and represent a major source of type 1 IFN post exposure to viral infections or Toll-Like Receptor 9 (TLR9) or TLR7 specific ligands. The goal of this proposal is to examine the effects of chronic viral infection on pDC cell function and how these effects contribute to viral persistence and susceptibility to a secondary infection. My doctoral and post-doctoral research that focused on innate and adaptive immune responses during viral infection led to an impressive publication record. I am skilled in the research techniques outlined in my current research proposal. While my preliminary work focused on acute viral infection, my proposal aims to investigate how chronic viral infections influence innate antiviral immune responses with aging. This novel field of investigation has important clinical relevance for an aging population increasingly burdened with chronic viral infection. Results from the experiments outlined in this proposal will provide insight on the influence of aging on innate immune responses during chronic viral infections. Lastly, I envision the proposed work to serve as a spring board that will launch a career as an independently funded scientist. In continuing to directly plan and execute experiments, my ability to think critically about biomedical investigation will be further refined and will lead to additional hypotheses which can be tested as part of a future grant application (e.g., R01). I resolutely believe that I have the talent and motivation to become a successful investigator in aging and I strongly believe that my work in aging and immunity will help in the understanding and treatment of chronic viral infections. Receipt of a K01 Mentored Research Scientist Development Award will allow me to achieve my primary career goal of becoming an expert and leader in the field of aging and viral immunity, who, by focusing on the complex relationship between aging and altered immune responses, will make important research contributions that will ultimately translate into improving the functional status of older persons. Under the guidance of my primary mentorship team, I have structured the following career development activities to support my primary career goal. Through my academic training and work experiences to date, I have obtained the essential underpinnings for applying immunologic methods to aging research. Given this strong foundation, I plan to focus on the operational side of my training, spending the largest proportion of my time with hands-on research training, complemented by highly focused didactic training targeting specific areas that are currently deficient. Therefore, the proposed career development plan is designed to give me the required tools to develop into a highly competitive, independent researcher in the field of aging. In addition to the experience that I will gain from executing the research plan and interacting with the mentorship team, I have proposed specific course work through the first two years of the award period that will help me short-term and long-term goals.

Public Health Relevance

At present, over 170 million people are infected by hepatitis C virus (HCV) (1). Acute HCV infection is asymptomatic, making the early stages of infection very difficult to diagnose. A hallmark feature of HCV infection is its tendency towards becoming a persistent, chronic infection, with at least 75% of acute infections becoming chronic. Chronic infection is often associated with significant liver disease, especially chronic active hepatitis, cirrhosis, and hepatocellular carcinoma (1). Chronic liver disease and cirrhosis are the tenth leading causes of death in the United States (2). As life expectancy in developed countries continues to increase, so has the number of elderly patients who have liver disease, with the most common cause of chronic liver disease being HCV (57% of cases) (2). With an aging population and chronic liver disease becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to improve our understanding of the dynamics of innate and adaptive immune responses during chronic viral infection and the relationship of these responses to viral clearance. As the innate immune response is the first line of defense against pathogens, it is imperative to elucidate how aging modifies innate immunity and contributes to chronic viral persistence. Plasmacytoid dendritic cells (pDCs) play a pivotal role in detection of foreign pathogens and represent a major source of type 1 IFN post exposure to viral infections or Toll-Like Receptor 9 (TLR9) or TLR7 specific ligands. Our preliminary experiments investigated whether aging affects innate pDC function during acute viral infection. Our results demonstrate that aged pDCs manifest defective TLR9 primary immune responses during acute viral infection. Impaired pDC function in aged hosts results in decreased production of type 1 IFNs as well as increased mortality and morbidity during HSV-2 viral infection. The goal of this proposal is to examine the effects of chronic viral infection on pDC cell function and how these effects contribute to viral persistence and susceptibility to a secondary infection. Specifically, we will employ murine models to test the hypothesis that aging decreases innate anti-viral immune responses and thereby contributes to the establishment and persistence of chronic viral infections.